20-33811394-C-A

Variant names:

• chr20-33811394-C-A
• rs2626522
• NM_176812.5:c.-75C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_176812.5(CHMP4B):​c.-75C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000922 in 1,084,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: CHMP4B NM_176812.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 0 publications found

Genes affected

CHMP4B (HGNC:16171): (charged multivesicular body protein 4B) This gene encodes a member of the chromatin-modifying protein/charged multivesicular body protein (CHMP) protein family. The protein is part of the endosomal sorting complex required for transport (ESCRT) complex III (ESCRT-III), which functions in the sorting of endocytosed cell-surface receptors into multivesicular endosomes. The ESCRT machinery also functions in the final abscisson stage of cytokinesis and in the budding of enveloped viruses such as HIV-1. The three proteins of the CHMP4 subfamily interact with programmed cell death 6 interacting protein (PDCD6IP, also known as ALIX), which also functions in the ESCRT pathway. The CHMP4 proteins assemble into membrane-attached 5-nm filaments that form circular scaffolds and promote or stabilize outward budding. These polymers are proposed to help generate the luminal vesicles of multivesicular bodies. Mutations in this gene result in autosomal dominant posterior polar cataracts.[provided by RefSeq, Oct 2009]

ZNF341-AS1 (HGNC:50736): (ZNF341 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP4B	NM_176812.5	c.-75C>A		5_prime_UTR_variant	Exon 1 of 5	ENST00000217402.3	NP_789782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP4B	ENST00000217402.3	c.-75C>A		5_prime_UTR_variant	Exon 1 of 5	1	NM_176812.5	ENSP00000217402.2
ZNF341-AS1	ENST00000824838.1	n.259+669G>T		intron_variant	Intron 1 of 3
ZNF341-AS1	ENST00000443171.7	n.-247G>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084638 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 520128

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21616

American (AMR) AF: 0.00 AC: 0 AN: 7902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13824

East Asian (EAS) AF: 0.0000395 AC: 1 AN: 25300

South Asian (SAS) AF: 0.00 AC: 0 AN: 31294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2892

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 907158

Other (OTH) AF: 0.00 AC: 0 AN: 43364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.77
PhyloP100		-0.018
PromoterAI		-0.0042	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2626522; hg19: chr20-32399200;